Sonogashira reaction mechanisms

The original Sonogashira reaction uses copper(l) iodide as a co-catalyst, which converts the alkyne in situ into a copper acetylide. In a subsequent transmeta-lation reaction, the copper is replaced by the palladium complex. The reaction mechanism, with respect to the catalytic cycle, largely corresponds to the Heck reaction.Besides the usual aryl and vinyl halides, i.e. bromides and iodides, trifluoromethanesulfonates (triflates) may be employed. The Sonogashira reaction is well-suited for the synthesis of unsymmetrical bis-2xy ethynes, e.g. 23, which can be prepared as outlined in the following scheme, in a one-pot reaction by applying the so-called sila-Sonogashira reaction ... 

The mechanism of the Sonogashira reaction has not yet been established clearly. This statement, made in a 2004 publication by Amatore, Jutand and co-workers, certainly holds much truth [10], Nonetheless, the general outline of the mechanism is known, and involves a sequence of oxidative addition, transmetalation, and reductive elimination, which are common to palladium-catalyzed cross-coupling reactions [6b]. In-depth knowledge of the mechanism, however, is not yet available and, in particular, the precise role of the copper co-catalyst and the structure of the catalytically active species remain uncertain [11, 12], The mechanism displayed in Scheme 2 includes the catalytic cycle itself, the preactivation step and the copper mediated transfer of acetylide to the Pd complex and is based on proposals already made in the early publications of Sonogashira [6b]. 

Scheme 2. Mechanism of the Sonogashira reaction for Pd/ Cu-catalyzed cross-coupling of sp2-C halides with terminal acetylenes.

Bohm, V. P. W., Herrmann, W. A. Coordination chemistry and mechanisms of metal-catalyzed C-C coupling reactions, 13 a copper-free procedure for the palladium-catalyzed Sonogashira reaction of aryl bromides with terminal alkynes at room temperature. Eur. J. Org. Chem. 2000,3679-3681. 

Scheme 14. (a) Sonogashira cross-coupling reaction mechanism, (b) Click chemistry [2 + 3]... 

In copper-free Sonogashira coupling the competition of ligand and amine base determines the reaction mechanism. The oxidative addition of Arl with (Ph3P)4Pd is faster when amine is present. With the proposed mechanisms the efficiency of PhsP > PhsAs is explained. 

Some of the optimized procedures for Stille and Sonogashira reactions involve the addition of copper cocatalysts to accelerate the cross-coupling procedures. A word of caution should be provided on the role of these additives in Pd-catalyzed amination procedures. Beletskaya and Davydov have reported the arylation of benzotriazole and of diary-lamines in polar organic or aqueous organic solvents using a combination of palladium and copper as catalyst.The arylation of amino acids has been reported under similar conditions.However, these reaction conditions are similar to classic Ullmann procedures for the synthesis of arylamines, except for the addition of palladium to the reaction mixture. In one case, subsequent work showed that the palladium species was not an essential component and that copper alone was the true catalyst in their reactions. An unusual accelerating effect of amino acid coordination to copper was used to explain the low-temperature Ullmann conditions. Beletskaya, however, showed that lower yields and a mixture of N1 and N2 arylation products were observed from the reactions of benzotriazole in the absence of copper and no reaction was observed in the absence of palladium. The conditions for this chemistry are, however, distinct enough from those of the majority of the aryl halide aminations to support the idea that a different mechanism may operate. 

The expanded use of the term Sonogashira reflects that it is not only important to develop a new reaction, but that it at least equally relevant to hansform it into a reliable and convenient methodology for organic synthesis. Since its inception, many variations of this transformation have been examined. Thus, various ligands, metal complexes, electrophiles, alkynes and bases were among others examined. In this context, it is somewhat counterintuihve to reahze that the mechanism of Sonogashira reactions has received little attention until recently. 

No additional phosphines or cooper salts were required, and InCfi itself catalyzed this transformation. Additional studies are required in order to carefully evaluate the mechanism of this transformation, which undoubtedly is different from that of the palladium-mediated Sonogashira reactions. Nonetheless, the simplicity and activity of the catalytic system, as well as its generality with respect to the nature of the leaving group, renders this a promising alternative for the synthesis of internal alkynes. 

In the next chapter we will discuss the use of alkynes as nucleophiles. From the reaction mechanism for Sonogashira reactions, the in situ-formed alkynylcopper intermediate should do transmetalation with palladium center and followed by reductive elimination, which is similar to the carbonylative reactions described in this chapter. 

In this chapter, we have discussed the carbonylative Sonogashira reaction of organohalides and their synthetic applications. Palladium-catalysts are still the main catalysts in this area. From the mechanism point of view, the same as the... 

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